Raoul S. Concepcion, MD, FACS: This is a nice segue. We’ve talked about the biopsy to best determine who needs active therapy versus who needs active surveillance. We know that there is going to be a group of people who are going to be diagnosed with higher-grade, higher-volume disease. They will get managed however they will be managed. We’re not here to discuss that. And then when they do get the biochemical recurrence, they get started on ADT—whether it be monotherapy or complete androgen blockade. We know that there is a subsegment of those people that will progress to this diagnosis of castration-resistant prostate cancer.

I think this has been what we’ve been talking about for a couple of years. And Evan, I know that your name gets brought up in this paper of 2600 patients, for a failed trial, where one-third of them were metastatic and people didn’t even know about it. I know you’ve done a heck of a lot better work than that, but feeding off that, I think we are understanding now that even when patients do progress to CRPC, part of this is urology’s fault—we didn’t identify metastatic disease early enough.

Evan Y. Yu, MD: The point that you’re bringing up is that when you have somebody on ADT and their PSA starts to rise, if you image them sooner, you might have this m0 CRPC space. If you image them later, in most of these patients, you can have radiographically detectable metastases. With newer imaging—for things like PSMA-PET scans or FACBC—you might be able to detect metastatic lesions as with a PSA in the 0.2 ng/mL-to-0.5 ng/mL range. So, M0 CRPC basically means “micrometastatic disease.” It’s a clinical disease state that will be a moving target on how large that disease state will be based upon how good our imaging is. It could move the bar on how we treat these patients. Should we be treating them with systemic therapies earlier by finding it earlier? We don’t know that that adds benefit.

More likely than not, people will want to consider utilizing these imaging modalities to say, “We found an oligometastasis earlier that we couldn’t find on a normal computed tomography scan and bone scan.” What if we design a trial to respond to that by doing more aggressive surgery, by doing more radiation, by adding in systemic therapy combinations with ADT, or maybe chemotherapy, or novel second-generation hormone androgen receptor pathway inhibitors?

It’s really quite an open field for investigation right now. The goal is, we’re trying to help our patients, cure more people, and help people live longer. But we do have to keep in mind that there’s no free lunch in life. These drugs have toxicity. And while we combine these drugs together, our goal is just to wipe out all the disease. But we have to do the studies to ensure that we’re doing the right thing for the patient and we’re not just being ultra-aggressive—giving more toxicity and not actually helping more people. We just don’t know yet. We have to do the research studies.

Michael A. Carducci, MD, FACP: I think there are a lot of nuances, too, with how you get to that state. It could be wide and varied in how you take newer data. What do you do for hormone-sensitive disease? It’s metastatic. How do you decide whether you give abiraterone or docetaxel, based on emerging data? You’ve got low-volume disease. You’ve got high-volume disease. Is this the first time you see metastatic disease or did this person have local therapy and now it grew over time? These are all very nuanced situations, and everybody has their own sense of what might be the latest therapy. But as Evan said, these are areas that we have to focus on and see what the right approach is.

Raoul S. Concepcion, MD, FACS: As we move down this continuum of prostate cancer, about 8% to 10% of patients actually will present or will walk in with metastatic prostate cancer but have never been exposed to ADT. And we know that, based upon the CHAARTED trial and the STAMPEDE trial, it seems that for patients with higher-volume metastatic disease, the combination of ADT and 6 cycles of docetaxel has better outcomes in terms of overall survival and delaying progression to CRPC. There are data now that have been presented at the 2017 ASCO Annual Meeting, this year, looking at an extension of STAMPEDE with ADT/abiraterone. Evan, do you want to comment on that?

Evan Y. Yu, MD: Yes. There are data with another arm in STAMPEDE where the patients received ADT and abiraterone. STAMPEDE is a trial where there’s a very heterogenous group of patients—they’re not all metastatic disease patients and they didn’t pre-specify breakdown of what we call high-volume versus low-volume metastatic disease. They just have the M1 disease state. And there’s a substantial proportion of patients that are M0, meaning they had, maybe, node-positive disease, surgery, or biochemical recurrence. And what they showed is a significant survival benefit for the overall population by adding abiraterone to ADT.

If you look at the subgroups, the hazard ratio for the M0 population does slightly cross 1. We have to consider the side effects versus the potential benefits there, but it all depends upon how you view the data. There are some people who say it was statistically powered to take the entire population, and there are other people who will focus on the subgroups. I think the other thing to consider is the LATITUDE trial. That’s another trial that shows a dramatic benefit with abiraterone for patients with new metastatic prostate cancer.

I think the reassuring thing is there’s not just 1 trial, it’s multiple trials. The data are real. They have been proven, shown, and confirmed back-to-back. That’s just another option for our patients. Should we be giving them ADT with docetaxel or ADT with abiraterone? There’s no direct head-to-head comparison yet. I would say they’re both reasonable standards of care moving forward.

Michael A. Carducci, MD, FACP: I designed that trial in 1999. We could never get it done—hormones/ketoconazole versus hormones/docetaxel. Now is the time for that, but we don’t know whether adding all 3 of them together would be the other approach that people would want to ask for. But again, is that too much therapy? Should you take docetaxel for high-volume or in visceral disease?

Abiraterone is a very effective drug and can work on all those patients. I think we just have to sort out these data. We have to look at some of the subgroups, as Evan said, and try to figure out what’s going to move forward. Abiraterone is easier to tolerate in most people’s minds, so they might just quickly shift over that way. In other cases, it might be a cost thing. If you have to pay out-of-pocket for 2 to 3 years, considering the cost of abiraterone, it might be easier just to get your docetaxel in quickly and know that it’s going to translate to a survival advantage as well.

Transcript Edited for Clarity

Transcript:

Raoul S. Concepcion, MD, FACS: This is a nice segue. We’ve talked about the biopsy to best determine who needs active therapy versus who needs active surveillance. We know that there is going to be a group of people who are going to be diagnosed with higher-grade, higher-volume disease. They will get managed however they will be managed. We’re not here to discuss that. And then when they do get the biochemical recurrence, they get started on ADT—whether it be monotherapy or complete androgen blockade. We know that there is a subsegment of those people that will progress to this diagnosis of castration-resistant prostate cancer.

I think this has been what we’ve been talking about for a couple of years. And Evan, I know that your name gets brought up in this paper of 2600 patients, for a failed trial, where one-third of them were metastatic and people didn’t even know about it. I know you’ve done a heck of a lot better work than that, but feeding off that, I think we are understanding now that even when patients do progress to CRPC, part of this is urology’s fault—we didn’t identify metastatic disease early enough.

Evan Y. Yu, MD: The point that you’re bringing up is that when you have somebody on ADT and their PSA starts to rise, if you image them sooner, you might have this m0 CRPC space. If you image them later, in most of these patients, you can have radiographically detectable metastases. With newer imaging—for things like PSMA-PET scans or FACBC—you might be able to detect metastatic lesions as with a PSA in the 0.2 ng/mL-to-0.5 ng/mL range. So, M0 CRPC basically means “micrometastatic disease.” It’s a clinical disease state that will be a moving target on how large that disease state will be based upon how good our imaging is. It could move the bar on how we treat these patients. Should we be treating them with systemic therapies earlier by finding it earlier? We don’t know that that adds benefit.

More likely than not, people will want to consider utilizing these imaging modalities to say, “We found an oligometastasis earlier that we couldn’t find on a normal computed tomography scan and bone scan.” What if we design a trial to respond to that by doing more aggressive surgery, by doing more radiation, by adding in systemic therapy combinations with ADT, or maybe chemotherapy, or novel second-generation hormone androgen receptor pathway inhibitors?

It’s really quite an open field for investigation right now. The goal is, we’re trying to help our patients, cure more people, and help people live longer. But we do have to keep in mind that there’s no free lunch in life. These drugs have toxicity. And while we combine these drugs together, our goal is just to wipe out all the disease. But we have to do the studies to ensure that we’re doing the right thing for the patient and we’re not just being ultra-aggressive—giving more toxicity and not actually helping more people. We just don’t know yet. We have to do the research studies.

Michael A. Carducci, MD, FACP: I think there are a lot of nuances, too, with how you get to that state. It could be wide and varied in how you take newer data. What do you do for hormone-sensitive disease? It’s metastatic. How do you decide whether you give abiraterone or docetaxel, based on emerging data? You’ve got low-volume disease. You’ve got high-volume disease. Is this the first time you see metastatic disease or did this person have local therapy and now it grew over time? These are all very nuanced situations, and everybody has their own sense of what might be the latest therapy. But as Evan said, these are areas that we have to focus on and see what the right approach is.

Raoul S. Concepcion, MD, FACS: As we move down this continuum of prostate cancer, about 8% to 10% of patients actually will present or will walk in with metastatic prostate cancer but have never been exposed to ADT. And we know that, based upon the CHAARTED trial and the STAMPEDE trial, it seems that for patients with higher-volume metastatic disease, the combination of ADT and 6 cycles of docetaxel has better outcomes in terms of overall survival and delaying progression to CRPC. There are data now that have been presented at the 2017 ASCO Annual Meeting, this year, looking at an extension of STAMPEDE with ADT/abiraterone. Evan, do you want to comment on that?

Evan Y. Yu, MD: Yes. There are data with another arm in STAMPEDE where the patients received ADT and abiraterone. STAMPEDE is a trial where there’s a very heterogenous group of patients—they’re not all metastatic disease patients and they didn’t pre-specify breakdown of what we call high-volume versus low-volume metastatic disease. They just have the M1 disease state. And there’s a substantial proportion of patients that are M0, meaning they had, maybe, node-positive disease, surgery, or biochemical recurrence. And what they showed is a significant survival benefit for the overall population by adding abiraterone to ADT.

If you look at the subgroups, the hazard ratio for the M0 population does slightly cross 1. We have to consider the side effects versus the potential benefits there, but it all depends upon how you view the data. There are some people who say it was statistically powered to take the entire population, and there are other people who will focus on the subgroups. I think the other thing to consider is the LATITUDE trial. That’s another trial that shows a dramatic benefit with abiraterone for patients with new metastatic prostate cancer.

I think the reassuring thing is there’s not just 1 trial, it’s multiple trials. The data are real. They have been proven, shown, and confirmed back-to-back. That’s just another option for our patients. Should we be giving them ADT with docetaxel or ADT with abiraterone? There’s no direct head-to-head comparison yet. I would say they’re both reasonable standards of care moving forward.

Michael A. Carducci, MD, FACP: I designed that trial in 1999. We could never get it done—hormones/ketoconazole versus hormones/docetaxel. Now is the time for that, but we don’t know whether adding all 3 of them together would be the other approach that people would want to ask for. But again, is that too much therapy? Should you take docetaxel for high-volume or in visceral disease?

Abiraterone is a very effective drug and can work on all those patients. I think we just have to sort out these data. We have to look at some of the subgroups, as Evan said, and try to figure out what’s going to move forward. Abiraterone is easier to tolerate in most people’s minds, so they might just quickly shift over that way. In other cases, it might be a cost thing. If you have to pay out-of-pocket for 2 to 3 years, considering the cost of abiraterone, it might be easier just to get your docetaxel in quickly and know that it’s going to translate to a survival advantage as well.